ABSTRACT Early in human life, the gut is colonized by a complex microbiome that includes dynamic interactions between the host, bacterial microbiome and virome (community of eukaryotic viruses and bacteriophage). Alterations within these microbial communities during early infant development may have long term health impacts. However, very little is known about maternal factors that drive virome acquisition and dynamics in infants. Breastfeeding provides nutrition and immune protection to the infant, but is also known to be a major route of mother-to-child transmission of some viruses. HIV infection can be transmitted through this route, and yet current guidelines recommend that HIV-positive women take antiretroviral treatment (ART) and breastfeed their infants because the health benefits outweigh the risk of HIV transmission. Infant morbidity and mortality remains higher in HIV-exposed uninfected infants compared to HIV-unexposed infants, and we hypothesize that differences in the breastmilk virome of HIV-infected women may play a role. Studies in HIV-infected adults and SIV-infected primate models demonstrate that the profound virome alterations are associated with HIV/AIDS disease progression. Thus, there is a critical need to understand the impact of maternal HIV disease progression as well as the role of maternal antiretroviral treatment on infant virome acquisition early in life. We will first leverage unique archived samples to demonstrate that the maternal virome is altered by effects of HIV infection. Specifically, we will test the hypothesis that immune status and ART impact the virome of HIV- infected mothers and we will conduct a retrospective case-control study to test the hypothesis that maternal virome profiles are associated with infant health outcomes. In addition, we aim to understand the impact of maternal HIV infection on virome acquisition in infants using prospective studies that allow us to sample both the mother and infant over time. We propose to characterize the mother-child virome interactions and test the hypothesis that perturbations in the maternal virome, due to the effects of HIV infection including CD4 count and use of ART, impact the composition of the infant virome. Further, we will determine associations between infant virome and infant health outcomes. These findings will have broad implications to infant health and development, and direct clinical relevance for current HIV treatment practices.